TET1 promotes growth of T-cell acute lymphoblastic leukemia and can be antagonized via PARP inhibition

Leukemia. 2021 Feb;35(2):389-403. doi: 10.1038/s41375-020-0864-3. Epub 2020 May 15.

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer characterized by skewed epigenetic patterns, raising the possibility of therapeutically targeting epigenetic factors in this disease. Here we report that among different cancer types, epigenetic factor TET1 is highly expressed in T-ALL and is crucial for human T-ALL cell growth in vivo. Knockout of TET1 in mice and knockdown in human T cell did not perturb normal T-cell proliferation, indicating that TET1 expression is dispensable for normal T-cell growth. The promotion of leukemic growth by TET1 was dependent on its catalytic property to maintain global 5-hydroxymethylcytosine (5hmC) marks, thereby regulate cell cycle, DNA repair genes, and T-ALL associated oncogenes. Furthermore, overexpression of the Tet1-catalytic domain was sufficient to augment global 5hmC levels and leukemic growth of T-ALL cells in vivo. We demonstrate that PARP enzymes, which are highly expressed in T-ALL patients, participate in establishing H3K4me3 marks at the TET1 promoter and that PARP1 interacts with the TET1 protein. Importantly, the growth related role of TET1 in T-ALL could be antagonized by the clinically approved PARP inhibitor Olaparib, which abrogated TET1 expression, induced loss of 5hmC marks, and antagonized leukemic growth of T-ALL cells, opening a therapeutic avenue for this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Proliferation
  • DNA Methylation*
  • DNA-Binding Proteins / physiology*
  • Gene Expression Regulation, Leukemic*
  • Histones
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / metabolism*
  • Phthalazines / pharmacology*
  • Piperazines / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins / physiology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • DNA-Binding Proteins
  • Histones
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Proto-Oncogene Proteins
  • TET1 protein, mouse
  • histone H3 trimethyl Lys4
  • Mixed Function Oxygenases
  • TET1 protein, human
  • olaparib